Overview

Pathogenicity: Alzheimer's Disease : Not Classified
ACMG/AMP Pathogenicity Criteria: PM1, PM2, PM5, PP2, PP3
Position: (GRCh38/hg38):Chr14:73217128 G>C
Position: (GRCh37/hg19):Chr14:73683836 G>C
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: GGA to CGA
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 11

Findings

This variant was identified in a genetic screen of 103 Spanish patients with early onset Alzheimer’s disease (AD) or fronto-temporal dementia (Ramos-Campoy et al., 2020). Whole-exome sequencing revealed the variant in a 50-year-old Spanish woman with dementia who had been suffering from episodic memory lapses, diminished language fluency, and word-finding difficulties for four years. Her APOE genotype was E3/E3. Of note, her mother’s cognition began declining at age 50, and that of her maternal uncle at age 58. The mutation was absent from the gnomAD variant database.

Neuropathology
Neuropathological data are unavailable, but a brain MRI of the proband revealed bilateral, fronto-temporo-parietal atrophy. Measurements of cerebrospinal fluid biomarkers were consistent with AD.

Biological Effect
The biological effects of this variant are unknown, but several in silico algorithms predicted the substitution to be deleterious, including CADD (Ramos-Campoy et al., 2020, Xiao et al., 2021). Moreover, a cryo-electron microscopy study of the atomic structure of γ-secretase bound to an APP fragment indicates that G378 forms part of one of two PSEN1 β-strands induced by APP binding. These strands, together with an APP β-strand, form a hybrid, three-stranded β–sheet that appears to be indispensable for cleavage (Zhou et al., 2019; Jan 2019 news).

Following the ACMG guidelines (Richards et al., 2015), Ramos-Campoy and colleagues classified it as likely pathogenic (Ramos-Campoy et al., 2020).

Pathogenicity

Alzheimer's Disease : Not Classified*

*This variant fulfilled some ACMG-AMP criteria, but it was not classified by Alzforum, because data for either a pathogenic or benign classification are lacking: only one affected carrier has been reported without co-segregation data, and the variant is absent—or very rare—in the gnomAD database.

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

PM1-S

Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation. G378R: Variant is in a mutational hot spot and cryo-EM data suggest residue is of functional importance.

PM2-M

Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. *Alzforum uses the gnomAD variant database.

PM5-M

Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.

PP2-P

Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.

PP3-P

Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.). *In most cases, Alzforum applies this criterion when the variant’s PHRED-scaled CADD score is greater than or equal to 20.

	Pathogenic (PS, PM, PP)			Benign (BA, BS, BP)
Criteria Weighting	Strong (-S)	Moderate (-M)	Supporting (-P)	Supporting (-P)	Strong (-S)	Strongest (BA)

Last Updated: 22 Feb 2022

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References

News Citations

Paper Citations

Ramos-Campoy O, Antonell A, Falgàs N, Balasa M, Borrego-Écija S, Rodríguez-Santiago B, Datta D, Armengol L, Fernández-Villullas G, Bosch B, Olives J, Muñoz-García C, Castellví M, Tort-Merino A, Sánchez-Valle R, Lladó A. Screening of dementia genes by whole-exome sequencing in Spanish patients with early-onset dementia: likely pathogenic, uncertain significance and risk variants. Neurobiol Aging. 2020 Sep;93:e1-e9. Epub 2020 Feb 18 PubMed.
Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.
Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015 May;17(5):405-24. Epub 2015 Mar 5 PubMed.

Mutations

PSEN1 G378R

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